Nominate A Living Woman Biologist For A Nobel Prize And Justify Your Choice

Mary-Claire King is known for many things, a geneticist, a mother, a teacher, and a human activist. These personality traits make Mary the astonishing and influential woman she is today. Her many research projects have a significant impact on the world we live in today and the view the population has on evolution and on the most famous and deadliest disease, cancer. Hence, I am going to justify why King s work deserves a Nobel prize.

King s initial work was on the molecular similarities between chimpanzees and humans, to be able to compare these species you either consider the homologous proteins or nucleic acids, you then need to compare and determine the difference between amino acids sequence of the homologous proteins of both populations. Another method is microcomplement fixation and the third method, electrophoresis which looks at the alleles the two species share[1]. For this comparison, all of these methods were utilised and so human and chimpanzee proteins have now been compared efficiently, allowing an estimate on the degree of genetic similarity. This comparison by King is said to be unique due to its comparison at the organismal level, consequently, these species have been compared at the level of anatomy, ecology, physiology and behaviour. This allows the research to be concise and accurate and a quantitative and objective estimate of the genetic distance between the two species can be obtained. It was concluded that the evolutionary distance between the species is acute, and it was reported that 99% of amino acid sequence in humans and chimpanzees is identical[2]. On reflecting on the results, King realised that her research focused solely on protein-coding DNA and subsequently she came to the resolution that she should have included transcri ptional regulation of protein-coding genes in causing evolutionary changes, and so many mutations may have not been recorded. This has recently proven to be the case. It was highlighted that non-protein coding regions, which are called introns, have very high rates of mutations and are far more variable between humans and species that can be seen as closely related[2]. This was analysed and explained due to the confusion as to why there is a large difference between humans and chimpanzees physically and anatomically but on the other hand, the DNA and proteins sequences are so similar. It s been suggested that evolutionary changes in anatomy and the way of life are a result of changes in the mechanisms controlling the expression of genes rather than on sequence changes in proteins themselves. King is recognised for being audacious with her hypotheses, and this particular one shows the beginning of new discoveries and breakthrough research she will embark on, this hypothesis was said to be daring in that period of time with the current information on genetics and evolution.

Thereafter, King decided to target her knowledge of genetics to human rights work. In 1984, King worked with a non-governmental human rights organisation called Abuelas de Plaza de Mayo , this organisation aimed to find and rescue stolen children in the Argentine Dirty War that began in 1974 and lasted till 1983. The Grandmothers protested against the abduction of their grandchildren and attempted to gather information to try and identify the missing children, however, the new democratic government wanted proof on kinship and without King s aid, the grandmothers may have never been reunited with their grandchildren. With her knowledge of genetics, King used dental samples and genetics to identify these missing children, analysing their genes to match them with their biological parents. Specifically focusing on using the dental samples to locate mitochondrial DNA. Mitochondria has its own, unique DNA that is inherited from the mother of the family which is genetically similar, highly variable and present in all their children. This created a perfect link between the child and the maternal family. Thus allowing King to successfully identify 59 of the 500 missing children and help them return safely to their families[3].

She continued to use this technique for other human rights cases, often used to identify deceased individuals after conflict or war. A good example would be in 1993, when she used the dental sample technique to identify 750 killed individuals in the villages of El Mozote and El Salvador, collaborating with human rights organisations such as Physicians for Human Rights and Amnesty International[3]. Not only is King perceived as a breakthrough scientist that changed peoples perspective on genetics but she is also a dedicated human rights activist who has contributed to helping people and countries in need. In addition, her remarkable technique to study mitochondrial DNA is now widely used in dental practice to this day, highlighting that even her early work had a significant impact on the world of science.

During the 1970s, King focused specifically on breast and ovarian cancer and after analysing previous studies, there had been evidence that families with a documented history of disease have a much higher risk of having breast cancer. King was able to approach this problem differently to other scientists due to her background in mathematics and evolutionary biology, giving her the ability to analyse the evidence and come to a logical conclusion. Her theory was that certain cancers were linked to inherited genetic mutations causing families to have similar diseases. However, this theory was disregarded in the early 1970s, as most scientists believed that cancer was viral, for example, Epstein-Barr and Hepatitis B. Nevertheless, King pursued her hypothesis and came to a valid and accurate result.

For King to initiate her research she needed a grant, and the week leading up to this was painful, tough and unfavourable. The first week of April 1981 began badly for Mary-Claire. Her husband had just revealed that he was divorcing her for a young graduate student, and the following day her house was robbed, leaving King devastated. Finding it difficult to cope with the pressure of looking after her daughter and also the pressure of presenting her theory to be approved for a grant. Nonetheless, this chaotic week led to her finally receiving the grant and now, 37 years later, this has become the story of the discovery of inherited breast cancer.

King s research launched in the early 1980s and started to develop after conversing with the National Cancer Institute (NCI). In the 1980s, the NCI was surveying women across the United States as part of their study to discover the effects of birth control pills and oral contraceptives in the development of breast and ovarian cancer. They interviewed 1,500 women[4] and King was able to convince them to add some of her own questions to the study regarding the family history of the patient. In addition, King tested both genetic cancer inheritance models and non-genetic models to allow for a comparison, and then completed a cross-analysis of the data from the models and the NCI, producing an outstanding result models with evidence of an autosomal-dominant breast cancer trait explained all the cases of heritable breast cancer. [2] Thus highlighting that there is a mutated gene responsible for breast cancer in 4% of the tested patients. The theory formed was that both inherited and non-inherited forms of cancer are caused by mutations in the same genes. By this stage, King knew there was a breast cancer gene. However, it was hypothetical and the best way to prove it existed was to find it.

Thus, began the persistent search for the breast cancer gene. Many methods were utilised such as linkage disequilibrium analysis[2], involving the isolation of polymorphisms in DNA sequences that are shared among humans with the same phenotype. After 17 years, King finally located the gene, and in 1990 published the discovery of BRCA1, the breast cancer gene on chromosome 17. This article initiated the race to clone the BRCA1 gene. Unfortunately, King and her laboratory lost this race against Myriad Genetics in 1994. Regardless, she continued her research into BRCA1 and has already described multiple mutations that are present in breast cancer. This process of locating and cloning the gene, helped researchers to further understand how mutations in the gene can lead to cancer thus being an extremely beneficial discovery.

However, there was a downside. After Myriad Genetics successfully cloned the gene, they claimed a patent on BRCA1. They had the authority over what they did with it, and after a few months, this patent became a real burden for King. Eventually, Myriad demanded exclusive use of BRCA1, and even tried to prevent King from continuing her BRCA1 related research, nevertheless, she resisted and progressed with her studies. Myriad s biggest error was that it cost $3,000 for someone to be tested for the BRCA1 gene, with only one location to obtain this test[4]. For most women, they couldn t afford this price and it was not covered by insurance, resulting in Myriads failure in testing for the gene. Moreover, in 2013, King gained an advantage. The supreme court ruled that the patent would be terminated, pronouncing that genes are natural products and cannot be patented , along with Angelina Jolie s diagnoses of the inherited BRCA1 gene, spreading the word of breast and ovarian cancer prevention. Since then testing is widely available, the price has been reduced significantly and more people are aware of this particular gene.

A crucial issue that arises is the increase in a person s cancer risk the risk of obtaining breast cancer rises from 7% to 55-65% when you obtain the BRCA1 gene mutation and as for ovarian cancer, this risk increases from 1% to 3% if you have the BRCA2 mutation. Therefore, it is vital that doctors are able to recognise this gene and make proactive decisions on reducing this risk. Women who carry mutations in BRCA1 and 2, can receive surgical intervention which can lessen the risk of ovarian and breast cancer and overall reduce mortality. In particular risk-reducing salpingo-oophorectomy, a surgical procedure to remove the ovaries and the fallopian tubes by the age of 40 to eliminate almost all of the ovarian cancer risk and reduce breast cancer risk by half[4]. However, most women who are carriers of these mutations are only identified after their first diagnosis due to family history not being sufficient enough for genetic testing. To only identify this after someone has been diagnosed is seen as a failure of cancer prevention. Therefore, King made it her mission to prevent this and to diminish the number of women diagnosed with cancer. Based on their 20 years of experience dealing with mutations in BRCA1 and 2 it is now time for King and her lab to offer genetic screening of these genes to every woman from the age of 30 as part of routine medical care[6] with the support of US Preventive Services Task Force. Despite this, testing is not available for the entire female population due to the lack of data on risks for mutation carriers, yet this has been corrected as a recent study has provided evidence that supports offering BRCA1 and BRCA2 sequencing to all women.

King conducted a study of population-based screening on the Ashkenazi Jewish population of Israel to determine cancer risks to BRCA1 and 2 mutation carriers[6]. She chose this population due to its limited number of cancer-predisposing BRCA1 and 2 mutations. They tested more than 8000 healthy Ashkenazi Jewish men, as men themselves are unaffected by breast cancer making them a reliable study. The results showed that 175 of the 8000 men were identified as a carrier of BRCA1 and 2 mutations and this allowed King and her associates to offer genetic testing to all of the men s female relatives[6]. Population-based screening allows mutation carriers to be identified without physician referral or family involvement, thus seen as an independent strategy. This is fundamental as there is variability in practice around the world which is revealed through the study in Israel where only 35% of families with high rates of breast and ovarian cancer were previously referred for genetic counselling, even though there was already common knowledge of increased cancer risk due to BRCA1 and 2 and also the availability of free and accessible testing in the health system of the Jewish population. The use of population-based screening will overcome these obstacles and will provide many civilians with the help they need. It will require significant efforts to educate people and to also develop new counselling strategies, which needs high levels of investment. Nonetheless, this investment will not only save women s lives but also provide a model for other public health programmes in genomic medicine [6]. King s main belief was that women should have the right to know information regarding their own health and not to be protected from it, they should have the choice to learn if they do carry a mutation in their BRCA1 or 2 genes. Her confidence in this theory was visible through her constant determination to prove the presence of BRCA1 and to provide evidence that cancer can be genetical.

After King s discovery of the association BRCA1 and 2 has with breast and ovarian cancer, she continued to study the genetics of disease and applying her genetics knowledge to other purposes. She became the American Cancer Society Research Professor at the University of Washington where she progressed with her cancer research work, finding more and more links between genetics and other diseases and conditions, for example, deafness[3]. In 1991, King and her lab successfully mapped and cloned the first autosomal gene for inherited deafness and later called the gene DFNA1. Not only did King uncover this outstanding theory of the deafness gene but she is also interested in the study of schizophrenia. she stated that they had found evidence that many cases of schizophrenia can be traced back to mutations that occur during the development of the embryo , she also implied that these diseases are genetic in origin, but they are acquired conditions and not seen as hereditary. [7] King theorises that these new mutations diminish brain development and thus contribute to the pathogenesis of schizophrenia. She has also been seen to carry on her work with human evolution, and is studying the genome of Homo sapiens, explaining the diversity of human life due to the movement of ancestors from one place to another, taking their genes with them and passing their genetics on to their descendants in a new location.

To conclude, Mary-Claire King has had a tremendous impact on science and the overall beliefs people have of many issues including human evolution, cancer research and DNA. She has already received multiple awards during her life, for example, the Hudson Alpha Life Sciences Prize and the Lasker Award in 2014 due to her major contribution to not only science but public services[3]. Overall

I strongly believe that King should be nominated for a Noble prize not just based on her scientific research but also her humanitarian work with several organisations including Abuelas de Plaza de Mayo , and the combination of these two factors that makes her particular work inspirational and so, she is held in high esteem due to her use of genetic technology to expose violations of human rights.

Bibliography:

[1] http://science.sciencemag.org/content/188/4184/107

Accessed on 29.01.19, Evolution at two levels in Humans and Chimpanzees

[2] https://www.jax.org/news-and-insights/jax-blog/2017/february/mary-claire-king

Accessed on 29.01.19, Women in Science: Marie-Claire King

[3] https://embryo.asu.edu/pages/mary-claire-king-1946

Accessed on 29.01.19, Marie-Claire King 1946< , By Meilin Zhu, Published on 23.08.17

[4] https://www.nytimes.com/2015/02/10/science/mary-claire-kings-pioneering-gene-work-from-breast-cancer-to-human-rights.html

Accessed on 19.02.19, A Never-Ending Genetic Quest , By Claudia Dreifus, Published on 09.02.15

[5] https://www.businessinsider.com/mary-claire-king-and-the-impact-brca-genes-had-on-cancer-genetics-2017-11?r=USIR=T Accessed on 15.02.19, Over a 40-year career, this `stubborn scientist` helped change the way we think about cancer and genetics , By Lydia Ramsey, Published on 16.11.17

[6] https://jamanetwork.com/journals/jama/fullarticle/1902783?resultClick=3

Accessed on 15.02.19, Population-Based screening for BRCA1 and BRCA2 , Author: Marie-Claire King, Ephrat Ley-Lahad and Amnon Lahad, Published on 08.09.14

[7] https://www.eurekalert.org/pub_releases/2013-03/guf-gmk031413.php

Accessed on 18.02.19, Geneticist Mary-Claire King receives the 2013 Paul Ehrlich Prize , Published on 14.03.13